Type I and type II keratin genes and their proteins undergo a tight regulation in a tissue-specific, differentiation-related, and context-dependent fashion in epithelial cells. Most disease states, including cancer, involve a departure from normal physiology and are invariably accompanied by aberrations in cellular differentiation pathways and keratin regulation. In addition to a ubiquitous and critically important role of structural support, keratin proteins were recently found to impact several key signaling pathways in epithelia. Two recent studies point to a significant modulatory role for two partner keratin proteins, keratin 17 and keratin 5, in basal cell carcinoma and related basaloid skin tumors. This project aims at defining the mechanistic link between these keratins and tumorigenesis in skin, and explore whether it applies to other epithelial tissues. Our specific aims for this project will be as follows. In Aim 1, we will seek to define the molecular mechanism(s) through which keratin 17 enhances the expression of select cytokines and chemokines in Gli2-overexpressing, tumor-prone skin keratinocytes. In Aim 2, we will seek to define the mechanism(s) through which two variants in keratin 5 (Gly138Glu and Asp197Glu) enhance the risk of developing basal cell carcinoma. In Aim 3, we will explore whether keratin 17 impacts the skin and cervical tumors arising in transgenic mice constitutively expressing the E6 and E7 oncoproteins from human papillomavirus 16, and then investigate whether the mechanism(s) underlying keratin-dependent modulation of tumor growth are the same as those uncovered in basal cell carcinoma and basaloid skin tumors. The mechanistic insight acquired about novel determinants of tumor cell architecture and regulation may lead to the identification of new therapeutic targets in the fight against cancer.